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Archive - Aug 2019

Date

August 15th

Study Identifies Gene Mutation (in RABL3 Gene) Linked to Hereditary Pancreatic Cancer

Pancreatic cancer is one of the deadliest cancers with limited treatment options. It typically comes with an especially poor prognosis due to its lack of symptoms until advanced stages and its ability to resist many anticancer therapies. Identifying genes involved in its development may lead to earlier diagnoses and improved treatments. Now, a research team led by investigators at Massachusetts General Hospital (MGH), Brigham and Women's Hospital, and Dana-Farber Cancer Institute has found that a mutation in a particular gene is associated with hereditary forms of pancreatic cancer in one family studied. Approximately 10% of pancreatic cancer is believed to be hereditary (see discussion of pancreatic cancer in former US President Jimmy Carter's family below). The research group also uncovered a mechanism by which mutations such as the one they identified may contribute to the development of tumors. In their study, which was published online on August 12, 2019 in Nature Genetics, the researchers sequenced the genomes of a family in which multiple members had pancreatic cancer. The analyses revealed a mutation in the RAS oncogene family-like 3 (RABL3) gene. The article is titled “Mutations in RABL3 Alter KRAS Prenylation and Are Associated with Hereditary Pancreatic Cancer.” To assess the effects of this gene mutation, the investigators recapitulated it in zebrafish, a model which offers large populations for studying the impact of newly discovered genetic mutations on cancer risk. The fish carrying the mutation developed cancers at an accelerated rate and with greater frequency. Additional studies revealed that the protein expressed by RABL3 interacts with components of the RAS signaling pathway, which has been implicated in various forms of cancer and other conditions.

Variants in MS4A4A Gene Influence Levels of Soluble TREM2 and Affect Susceptibility to Alzheimer’s Disease; Results Suggest Increased Focus on Brain’s Immune Cells (Microglia)

An international team of researchers led by scientists at Washington University School of Medicine in St. Louis has identified a pair of genes that influence risk for both late-onset and early-onset Alzheimer's disease. Most genes implicated thus far in Alzheimer's affect neurons that transmit messages, allowing different regions of the brain to communicate with one another. But the newly identified genes affect an entirely different population of cells: the brain's immune cells. The findings, published online on August 14, 2019 in Science Translational Medicine, could provide scientists with new targets and a strategy for delaying the onset of Alzheimer's symptoms. The article is titled “The MS4A Gene Cluster Is a Key Modulator of Soluble TREM2 and Alzheimer’s Disease Risk.” The identified genes -- known as MS4A4A and TREM2 -- operate in the microglia (image), the brain's immune cells. The genes influence Alzheimer's risk by altering levels of TREM2, a protein that is believed to help microglia cells clear excessive amounts of the Alzheimer's proteins beta-amyloid and tau from the brain. "The findings point to a new therapeutic strategy," said co-senior investigator Carlos Cruchaga, PhD, a Professor of Psychiatry and Director of the NeuroGenomics and Informatics Group at Washington University School of Medicine. "If we can do something to raise levels of the TREM2 protein in the cerebrospinal fluid, we may be able to protect against Alzheimer's disease or slow its development." In this study, the researchers measured soluble TREM2 levels in the cerebrospinal fluid of 813 older adults, most of whom were ages 55 to 90. Of those subjects, 172 had Alzheimer's disease, 169 were cognitively normal, and another 183 had early mild cognitive impairment.

Lost in Translation: Researchers Discover Surprising Amount of Variation in tRNA Genes; Suggest Possible Role in Disease

A molecule called transfer ribonucleic acid (tRNA), is an essential component of the human genome that acts as a translator. It reads the genetic code and translates it into proteins - one of the key building blocks of the human body. When researchers and clinicians investigate the genome's relation to disease, they have traditionally focused on mutations in the code for proteins. But now researchers at Western University in Canada have shown that the genes encoding tRNAs can also have mutations that cause the code to be misread, and in greater numbers than previously thought. Think of it like a translator app on your phone - if it has errors in its software, the output is going to be all wrong, even if the original text is correct. The results of the new study were published online on August 13, 2019 in RNA Biology. The article is titled “Targeted Sequencing Reveals Expanded Genetic Diversity of Human Transfer RNAs.” "This actually changes the way we think about the genetic code," said lead author Mathew Berg, a PhD Candidate at Western's Schulich School of Medicine & Dentistry.

Researchers ID Possible Target Matrix Protein (Perlecan) in Effort to Halt Spread of Pancreatic Cancer

An international team of researchers has revealed how aggressive pancreatic cancer cells change their environment to enable easy passage to other parts of the body (metastasis) - the main cause of pancreatic cancer-related death. The researchers discovered that some pancreatic tumors produce more of a molecule called “perlecan” to remodel the environment around them, which helps cancer cells spread more easily to other parts of the body, and also protects them against chemotherapy. In a mouse model, the researchers showed that lowering the levels of perlecan reduced the spread of pancreatic cancer and improved response to chemotherapy. Led by Associate Professor Paul Timpson, PhD, Head of the Invasion and Metastasis Laboratory, and Thomas Cox, PhD, Leader of the Matrix and Metastasis Group, both at the Garvan Institute of Medical Research in Australia, the research may provide a promising new path to more effective treatment options for individuals with pancreatic and other cancers. The findings were published online on August 12, 2019 in Nature Communications. The open-access article is titled “CAF Hierarchy Driven by Pancreatic Cancer Cell p53-Status Creates a Pro-Metastatic and Chemoresistant Environment via Perlecan.”"Pancreatic cancer is very aggressive, and, by the time most cases are diagnosed, the tumor is often inoperable," says Associate Professor Timpson. "What we've discovered in this study is a two-pronged approach for treating pancreatic cancer that we believe will improve the efficiency of chemotherapy and may help reduce tumor progression and spread." Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia.

August 12th

Enterovirus Antibodies Detected in CSF of Acute Flaccid Myelitis (AFM) Patients; New Study Adds to Knowledge About Rare Condition

A new study analyzing samples from patients with and without acute flaccid myelitis (AFM) provides additional evidence for an association between the rare, but often serious, condition that causes muscle weakness and paralysis, and infection with non-polio enteroviruses. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, funded the research, which was conducted by collaborating investigators at Columbia University's Center for Infection and Immunity, the Centers for Disease Control and Prevention (CDC), and the University of California San Diego (UCSD). The findings were reported online on August 13, 2019 in the online journal mBio. The open-access article is titled “Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.” There have been 570 confirmed cases since the CDC began tracking AFM in August 2014. AFM outbreaks were reported to the CDC in 2014, 2016 and 2018. AFM affects the spinal cord and is characterized by the sudden onset of muscle weakness in one or more limbs. Spikes in AFM cases, primarily in children, have coincided in time and location with outbreaks of one enterovirus (EV) EV-D68 (image) and a related enterovirus, EV-A71. Both of these viruses typically cause mild respiratory illness from which most people recover fully. Despite the epidemiological link between enterovirus circulation and AFM cases, evidence of direct causality has not been found. The researchers first looked for direct evidence of enterovirus infection in the cerebrospinal fluid (CSF) of 13 children and one adult diagnosed with AFM in 2018. They also examined five CSF samples taken from people with other central nervous system diseases.

August 5th

Long-Term, Anti-Rejection-Drug-Free Tolearance of Pancreas Islets Cells Induced by Apoptotic Donor Leukocytes in Non-Human Primates; Anti-Rejection Drugs Completely Discontinued 21 Days After Transplant

For decades, immunologists have been trying to train the transplant recipient's immune system to accept transplanted cells and organs without the long-term use of anti-rejection drugs. New University of Minnesota preclinical research shows that this is now possible. In a study published online on August 2, 2019 in Nature Communications, researchers at the University of Minnesota Medical School's Department of Surgery and Schulze Diabetes Institute, collaborating with colleagues at Northwestern University, have maintained long-term survival and function of pancreatic islet transplants despite complete discontinuation of all anti-rejection drugs on day 21 after the transplant. The open-access article is titled “Long-Term Tolerance of Islet Allografts in Nonhuman Primates Induced by Apoptotic Donor Leukocytes.” This study was performed in a stringent preclinical transplant setting in nonhuman primates, one step away from humans. For many patients with end-stage organ failure, transplantation is the only effective and remaining treatment option. To prevent transplant rejection, recipients must take medications long-term that suppress the body's immune system. These immunosuppressive drugs are effective at preventing rejection over the short term; however, because anti-rejection drugs suppress all of the immune system nonspecifically, people taking these drugs face the risk of serious infections and even cancer. Additionally, non-immunological side effects of immunosuppression, such as hypertension, kidney toxicity, diarrhea, and diabetes diminish the benefits of transplantation.

August 3rd

Self-Sterilizing Polymer Proves Effective Against Drug-Resistant Pathogens

Researchers from North Carolina (NC) State University have found that an elastic polymer possesses broad-spectrum antimicrobial properties, allowing it to kill a range of viruses and drug-resistant bacteria in just minutes - including methicillin-resistant Staphylococcus aureus (MRSA). "We were exploring a different approach for creating antimicrobial materials when we observed some interesting behavior from this polymer and decided to explore its potential in greater depth," says Rich Spontak, PhD, co-corresponding author of a paper on the work and Distinguished Professor of Chemical and Biomolecular Engineering at NC State. "And what we found is extremely promising as an alternate weapon to existing materials-related approaches in the fight against drug-resistant pathogens. This could be particularly useful in clinical settings - such as hospitals or doctor's offices - as well as senior-living facilities, where pathogen transmission can have dire consequences." The polymer's antimicrobial properties stem from its unique molecular architecture, which attracts water to a sequence of repeat units that are chemically modified (or functionalized) with sulfonic acid groups. "When microbes come into contact with the polymer, water on the surface of the microbes interacts with the sulfonic acid functional groups in the polymer - creating an acidic solution that quickly kills the bacteria," says Reza Ghiladi, PhD, an Associate Professor of Chemistry at NC State and co-corresponding author of the paper. "These acidic solutions can be made more or less powerful by controlling the number of sulfonic acid functional groups in the polymer." The work was published online on July 17, 2019 in Materials Horizon.

August 1st

Discovery of Maturation Plasticity in Acute Myeloid Leukemia Cells May Redirect Research

Approximately 22,000 people will be diagnosed this year in the US with acute myeloid leukemia (AML), the second most common type of leukemia diagnosed in adults and children, and the most aggressive of the leukemias. Less than one third of AML patients survive five years beyond diagnosis. Researchers from Australia's Monash University have discovered a key reason why this disease is so difficult to treat and therefore cure. The study, led by Associate Professor Ross Dickins from the Australian Centre for Blood Diseases, was published online on August 1, 2019 in Cell Stem Cell. The article is titled “Interconversion Between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.” The paper identifies an important new concept relevant to clinicians involved in the diagnosis and treatment of AML patients. AML is characterised by an overproduction of immature white blood cells that fail to mature properly. These leukemia cells crowd the bone marrow, preventing it from making normal blood cells. In turn this causes anemia, infections, and if untreated, death. AML remains a significant health problem, with poor outcomes despite chemotherapy and stem cell transplantation. For decades it has been thought that AML growth is driven by a sub-population of immature cancer cells called “leukemia stem cells,” which lose their cancerous properties when they mature. Hence, there has been growing international interest in developing therapies aimed at forcing immature cancer cells to “grow up.” Using genetically engineered mouse models and human AML cells, Associate Professor Dickins and his Monash-led team have found that maturation of AML cells is not unidirectional as originally thought, but can instead be reversible.